bims-tremyl Biomed News
on Therapy resistance biology in myeloid leukemia
Issue of 2025–05–04
thirty-two papers selected by
Paolo Gallipoli, Barts Cancer Institute, Queen Mary University of London
  1. Prognostic impact of clonal representation of myelodysplasia-related gene mutations in acute myeloid leukemia.
  2. Clinical impact of tyrosine kinases related mutations in NPM1 mutated acute myeloid leukaemia: A report from the Northern Italy Leukaemia Group (NILG) multicentre randomized trial 02/06.
  3. Single-cell Transcriptional Atlas of Human Hematopoiesis Reveals Genetic and Hierarchy-Based Determinants of Aberrant AML Differentiation.
  4. β-Catenin interacts with canonical RBPs including MSI2 to associate with a Wnt signalling mRNA network in myeloid leukaemia cells.
  5. Characterization and Clinical Implications of p53 Dysfunction in Patients With Myelodysplastic Syndromes.
  6. Venetoclax plus modified-intensity Idarubicin and Cytarabine treatment as first-line treatment for newly diagnosed pediatric acute myeloid leukemia.
  7. Targeting FLT3 for treating diseases: FLT3 inhibitors.
  8. Outcomes of acute myeloid leukemia with KMT2A (MLL) rearrangement: a multicenter study of TROPHY group.
  9. Molecular monitoring versus standard clinical care in younger adults with acute myeloid leukaemia: results from the UK NCRI AML17 and AML19 randomised, controlled, phase 3 trials.
  10. Somatic TP53 Mutations Drive T and NK Cell Dysfunction in AML and Can be Rescued by Reactivating Wild Type p53.
  11. Clinical characteristics and therapeutic determinants of RUNX1::RUNX1T1 differ from those of CBFB::MYH11 acute myeloid leukemia.
  12. Impact of Post-Transplant Cyclophosphamide-Based GVHD Prophylaxis in Patients 70 years and Older: An Update from BMT CTN 1703.
  13. Hypomethylating agents plus venetoclax for high-risk MDS and CMML as bridge therapy to transplant: a GESMD study.
  14. A case series of oral decitabine-cedazuridine with venetoclax for blastic plasmacytoid dendritic cell neoplasm.
  15. Different features of acute myeloid leukemia stem cell quantification in intensively treated patients.
  16. A Phase II Trial of Geriatric Assessment-Guided Selection of Treatment Intensity in Older Adults With AML.
  17. Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia.
  18. DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition.
  19. Clonal hematopoiesis is associated with distinct rheumatoid arthritis phenotypes.
  20. Molecular predictors of venous and arterial thrombotic events in patients with myelofibrosis.
  21. Distinct transcriptional changes in hematopoietic progenitor subsets upon LPS-induced emergency granulopoiesis.
  22. Hematopoietic Stem Cell Transplantation Outcomes for High-Risk AML: A Report From the Children's Oncology Group.
  23. Impact of KIT mutation on efficacy of venetoclax and hypomethylating agents in newly diagnosed acute myeloid leukemia.
  24. Contemporary management paradigms and emerging therapeutics for myelodysplastic syndromes/neoplasms.
  25. Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia.
  26. Putting AML Differentiation States on the BoneMarrowMap.
  27. Is the bone marrow microenvironment the hidden catalyst in malignant haematopoiesis?
  28. Network-based clustering unveils interconnected landscapes of genomic and clinical features across myeloid malignancies.
  29. Mutant macrophages CHIP in to help solid tumors.
  30. Optimizing olverembatinib dose in chronic phase chronic myeloid leukemia.
  31. Cell cycle duration determines oncogenic transformation capacity.
  32. Pegylated Interferons: Still a Major Player for the Treatment of Myeloproliferative Neoplasms.
  1. Leukemia. 2025 Apr 28.
    Prognostic impact of clonal representation of myelodysplasia-related gene mutations in acute myeloid leukemia.
    Rabea Mecklenbrauck, Nora Borchert, Razif Gabdoulline, Piroska Poll, Carolin Funke, Maximilian Brandes, Louisa-Kristin Dallmann, Walter Fiedler, Jürgen Krauter, Arne Trummer, Bernd Hertenstein, Martin Müller, Michael Lübbert, Monika Schwalenberg, Andreas Voss, Nataliya Di Donato, Anke Bergmann, Verena Gaidzik, Konstanze Döhner, Hartmut Döhner, Arnold Ganser, Florian H Heidel, Felicitas R Thol, Michael Heuser.
      
    DOI:  https://doi.org/10.1038/s41375-025-02622-6
  2. Leuk Res. 2025 Apr 20. pii: S0145-2126(25)00062-1. [Epub ahead of print]153 107702
    Clinical impact of tyrosine kinases related mutations in NPM1 mutated acute myeloid leukaemia: A report from the Northern Italy Leukaemia Group (NILG) multicentre randomized trial 02/06.
    Gianluca Cavallaro, Silvia Salmoiraghi, Roberta Cavagna, Chiara Pavoni, Clara Belotti, Martina Milani, Elena Oldani, Marco Frigeni, Tamara Intermesoli, Anna Grassi, Renato Bassan, Orietta Spinelli, Alessandro Rambaldi, Federico Lussana.
      Co-mutational patterns play a role in the clinical outcome of nucleophosmin-1 (NPM1) mutated acute myeloid leukaemia (AML). Tyrosine kinase (TK) related gene mutations are included in these additional mutations, but their impact on prognosis of NPM1-mutated AML is unknown. We analyzed the outcomes of patients with NPM1 AML with TK related mutations treated with intensive chemotherapy in the prospective randomized trial NILG AML 02/06, with regards to NPM1-FLT3-ITD and NPM1-isolated. Data show that additional TK related mutations do not impact the favorable prognosis on NPM1-mutated AML, unlike NPM1-FLT3-ITD mutated AML, for which consolidation with allogeneic stem cell transplantation should be considered for all young and fit patients in first complete remission.
    DOI:  https://doi.org/10.1016/j.leukres.2025.107702
  3. Blood Cancer Discov. 2025 Apr 28. OF1-OF18
    Single-cell Transcriptional Atlas of Human Hematopoiesis Reveals Genetic and Hierarchy-Based Determinants of Aberrant AML Differentiation.
    Andy G X Zeng, Ilaria Iacobucci, Sayyam Shah, Amanda Mitchell, Gordon Wong, Suraj Bansal, David Chen, Qingsong Gao, Hyerin Kim, James A Kennedy, Andrea Arruda, Mark D Minden, Torsten Haferlach, Charles G Mullighan, John E Dick.
       SIGNIFICANCE: We present a single-cell reference atlas of human hematopoiesis and a computational tool for rapid mapping and classification of healthy and leukemic cells. Applied to AML, this has enabled single-cell analysis at the scale of hundreds of patient samples, revealing the full breadth of derailment of differentiation in AML. See related commentary by Berger and Penter, p. XX.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-24-0342
  4. Oncogene. 2025 Apr 30.
    β-Catenin interacts with canonical RBPs including MSI2 to associate with a Wnt signalling mRNA network in myeloid leukaemia cells.
    M Wagstaff, O Sevim, A Goff, M Raynor, H Park, E J Mancini, D T T Nguyen, T Chevassut, A Blair, L Castellano, S Newbury, B Towler, R G Morgan.
      Wnt/β-catenin signalling is important for normal hematopoietic stem/progenitor cell (HSPC) biology and heavily implicated in acute and chronic myeloid leukaemia (AML and CML). The central mediator β-catenin is an attractive therapeutic target in myeloid neoplasms however its targeting has been hampered by a poor characterisation of its molecular interactions in haematopoietic cells, which will differ from its network in solid tissues. Our previous β-catenin interactome study identified the significant enrichment of RNA-binding proteins (RBP) implying post-transcriptional roles for β-catenin in myeloid cells. To identify β-catenin interacting mRNAs we performed β-catenin RNA-immunoprecipitation coupled to RNA-sequencing (RIP-seq) and identified significantly enriched Wnt signalling pathway transcripts. Using β-catenin cross-linking immunoprecipitation (CLIP) we demonstrated a limited capacity for β-catenin to bind RNA directly, implying dependence on other RBPs. β-Catenin was found to interact with Musashi-2 (MSI2) in both myeloid cell lines and primary AML patient samples, where expression was significantly correlated. MSI2 knockdown reduced Wnt signalling output (TCF/LEF activity), through suppression of LEF-1 expression and nuclear localisation. Through both RIP and CLIP we demonstrate MSI2 binds LEF1 mRNA in a partly β-catenin dependent fashion, and may impact the post-transcriptional control of LEF-1 expression. Finally, we show that MSI2-mediated expansion of human HSPCs could be partly driven through LEF1 regulation. This is the first study to experimentally demonstrate functional crosstalk between MSI2 and Wnt signalling in human cells, and indicates potential novel post-transcriptional roles for β-catenin in a haematological context.
    DOI:  https://doi.org/10.1038/s41388-025-03415-y
  5. J Clin Oncol. 2025 May 02. JCO2402394
    Characterization and Clinical Implications of p53 Dysfunction in Patients With Myelodysplastic Syndromes.
    CALR Consortium
       PURPOSE: Tumor Protein 53 (p53) expressed from gene TP53 is a seminal tumor suppressor. We aimed to characterize mutational and nonmutational mechanisms of p53 dysfunction in myelodysplastic syndromes (MDS) and to investigate their clinical effect.
    PATIENTS AND METHODS: We analyzed a cohort of 6,204 patients with MDS and subsets of patients with available information on RNA sequencing of tumor cells (n = 109), high-dimensional phenotype of immune cells (n = 77), and multiomics analysis (RNA sequencing and proteomics) on single cells (n = 15). An independent validation was performed on 914 patients.
    RESULTS: Biallelic TP53 inactivation was a powerful driver of disease progression and identified high-risk patients, regardless of variant allele frequency. Monoallelic and biallelic inactivation represent disease stages occurring as a multihit process in MDS with TP53 mutations, thus potentially refining the optimal timing of therapeutic interventions in these patients. We identified a subset of MDS (5%) characterized by TP53 wild-type and hyperexpression of abnormal p53 protein in bone marrow progenitors that exhibit dismal outcome. These patients presented upstream p53 signaling aberrations in Pi3K cascade; RAS, WNT, and NF-KB pathways; and MDM2 gene amplification, together with a downstream dysregulation of p53 targets. MDS with p53 dysfunction displayed a distinct immune dysregulation involving myeloid-derived inflammation and impaired antigen presentation, which may be a driver of their poor prognosis and provide the groundwork for innovative immunotherapies.
    CONCLUSION: The identification of nonmutational p53 dysfunction in MDS may lay the foundation for a mechanistic classification of myeloid neoplasms, moving beyond a purely molecular stratification. The recognition of patients with p53 dysfunction is relevant to provide correct disease-risk assessment and interventions, as well as to refine the design of clinical trials.
    DOI:  https://doi.org/10.1200/JCO-24-02394
  6. Clin Cancer Res. 2025 Apr 28.
    Venetoclax plus modified-intensity Idarubicin and Cytarabine treatment as first-line treatment for newly diagnosed pediatric acute myeloid leukemia.
    Shiyuan Wang, Mingyan Jiang, Yaqin Wang, Lixian Chang, Beibei Zhao, Xiaoming Liu, Benquan Qi, Shuchun Wang, Tianfeng Liu, Xiaoyan Zhang, Yumei Chen, Fang Liu, Ye Guo, Xiaojuan Chen, Li Zhang, Yao Zou, Wenyu Yang, Ju Gao, Xiaofan Zhu, Min Ruan.
       PURPOSE: Venetoclax (VEN) has shown excellent activity in eliminating acute myeloid leukemia (AML) blasts in preclinical and clinical trials, but clinical data in pediatric newly diagnosed AML (ND-AML) remain limited. We evaluated VEN plus modified-intensity idarubicin and cytarabine chemotherapy (VIA) in childhood ND-AML.
    EXPERIMENTAL DESIGN: In an open-label, single-arm, multi-center prospective clinical trial, 65 ND-AML pediatric patients received VIA induction (VEN and modified-intensity cytarabine and idarubicin). Consolidation was guided on response to induction and individualized risk stratification. Primary end point was complete remission (CR) and measurable residual disease (MRD) response rates.
    RESULTS: After induction cycle 1, CR and MRD negativity was 90.8% and 78.5%, increasing to 96.8% and 87.3% following induction cycle 2. 28 (43.2%) patients underwent hematopoietic stem cell transplantation (HSCT) without engraftment failure. CBF AML [t(8;21) and inv(16)/t(16;16)] patients achieved a favorable response rate, but the median log10 reduction of transcript levels was suboptimal [-1.7 (cycle 1) and -2.6 (cycle 2) for RUNX1::RUNX1T1, -2.3 and -2.5 for CBFB::MYH11]. Disease relapse was frequently observed in KIT mutation, RUNX1::RUNX1T1 and CBFB::MYH11. The most common grade 3-4 toxicities were hematological toxicities and febrile neutropenia (FN). No treatment-related deaths occurred. With a median follow-up of 15.7 months, the estimated 12-month overall survival and event-free survival was 92.3% (95% CI 86.0-99.8) and 79.1% (95% CI 69.6-90.0). MRD negativity post cycle 1 correlated with superior long-term survival (P < 0.001).
    CONCLUSIONS: VIA regimen is highly effective and relatively safe in children with ND-AML, with deep remission and favorable survival outcomes.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-25-0479
  7. Drug Discov Today. 2025 Apr 25. pii: S1359-6446(25)00080-7. [Epub ahead of print] 104367
    Targeting FLT3 for treating diseases: FLT3 inhibitors.
    Qing-Yun Rong, Yu Lu, Wen Zhang, Guo-Wu Rao, Quan Zheng.
      FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) expressed mainly in hematopoietic stem and progenitor cells and often mutated in hematological tumors, such as acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). A variety of FLT3 inhibitors have been approved and adopted for the treatment of AML. However, these suffer resistance problems, and further studies are needed. Here, we review the current status of research on FLT3 inhibitors in AML, discuss the occurrence of resistance, and suggest approaches to overcome such resistance.
    Keywords:  AML; FLT3 inhibitor; gilteritinib
    DOI:  https://doi.org/10.1016/j.drudis.2025.104367
  8. Blood Cancer J. 2025 May 02. 15(1): 84
    Outcomes of acute myeloid leukemia with KMT2A (MLL) rearrangement: a multicenter study of TROPHY group.
    Ruoxuan Zhang, Huihong Huang, Yi Zhang, Yi Xia, Jiayu Huang, Chuanhe Jiang, Luxiang Wang, Haiyang Lu, Zengkai Pan, Gaoxiang Wang, Yang Yang, Yilei Ma, Xiaodong Mo, Wei Shi, Xiaoxia Hu, Yang Cao.
      Acute myeloid leukemia (AML) with KMT2A rearrangement (KMT2A-r) is associated with poor prognosis, but the benefit of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for KMT2A-r AML is unclear. We reviewed adult AML patients treated within the TROPHY group and identified 292 cases of KMT2A-r AML, 254 (87.0%) of whom achieved first complete remission (CR1) and 192 (75.6%) of CR1 patients underwent allo-HSCT. We show that allo-HSCT is an independent favorable prognostic factor in CR1 patients for both overall survival (OS) (hazard ratio [HR] = 0.56, 95% confidence interval [CI]: 0.45-0.69, P < 0.001) and cumulative incidence of relapse (CIR) (HR = 0.01, 95% CI: 0.005-0.04, P < 0.001). Among allo-HSCT recipients, survival outcomes were comparable between patients with KMT2A::MLLT3 and those with other 11q23/KMT2A rearrangements (3-year OS: 74.3% vs. 77.5%, P = 0.97; 3-year event-free survival [EFS]: 55.2% vs. 62.2%, P = 0.34; 3-year CIR: 24.4% vs. 20.8%, P = 0.32). Both multiparameter flow cytometry-based measurable residual disease (MFC-MRD) and KMT2A-r MRD determined by quantitative PCR prior to allo-HSCT were associated with worse transplant outcomes. Multivariable analysis identified detectable KMT2A-r MRD at allo-HSCT as a significant risk factor for reduced EFS (HR = 2.46, 95% CI: 1.32-4.60, P = 0.005). These findings confirm the survival benefit of allo-HSCT in adult patients with KMT2A-r AML and underscore the prognostic value of KMT2A-r MRD prior to transplantation.
    DOI:  https://doi.org/10.1038/s41408-025-01293-x
  9. Lancet Haematol. 2025 May;pii: S2352-3026(25)00037-7. [Epub ahead of print]12(5): e346-e356
    Molecular monitoring versus standard clinical care in younger adults with acute myeloid leukaemia: results from the UK NCRI AML17 and AML19 randomised, controlled, phase 3 trials.
    UK AML Research Network
       BACKGROUND: In patients with acute myeloid leukaemia treated with curative intent, the detection of measurable residual disease (MRD) generally confers a poor prognosis. This study aimed to identify whether altering treatment based on MRD results can improve survival.
    METHODS: In the UK NCRI AML17 and AML19 randomised, controlled, phase 3 trials, performed in the UK, Denmark, and New Zealand, we screened patients aged 16-60 years with newly diagnosed acute myeloid leukaemia for molecular markers suitable for disease monitoring, including NPM1 mutations and fusion genes. Patients with a marker were randomly assigned (2:1) to either sequential molecular MRD monitoring during treatment and for 3 years after, or standard clinical care only with no molecular monitoring. In the monitoring group, treating physicians decided whether and how to incorporate the MRD results into the patient's therapy, including in cases of MRD relapse. The primary endpoint was overall survival. Prespecified subgroup analysis of the primary outcome included analysis by molecular group (NPM1mut with FLT3-ITD, NPM1mut without FLT3-ITD, and fusion gene transcripts). Both trials were registered with ISRCTN, ISRCTN55675535 and ISRCTN78449203, and are completed.
    FINDINGS: In the AML17 trial, 1836 patients were enrolled between June 1, 2012 and Dec 31, 2014. In the AML19 trial, 965 patients were enrolled between Nov 9, 2015, and Jan 23, 2018. 637 patients were randomly assigned across both trials (289 to MRD monitoring and 144 to no monitoring in AML17 and 136 to MRD monitoring and 68 to no monitoring in AML19). With a median follow-up time of 4·9 years (IQR 3·6-5·9), overall survival at 3 years was 70% (95% CI 66-75) in patients in the monitoring group and 73% (68-80) in patients in the no-monitoring group. Meta analysis of the two studies showed no difference in overall survival (hazard ratio [HR] 1·11, 95% CI 0·83-1·49; p=0·25). In the pre-specified subgroup analysis of the primary endpoint, overall survival at 3 years in patients with both NPM1 and FLT3 internal tandem duplication (ITD) mutations was 69% (95% CI 60-79) in the monitoring group and 58% (45-74) in the no-monitoring group (HR 0·53, 95% CI 0·31-0·91; p=0·021). However there was no difference in survival by randomisation in patients with NPM1 mutations without FLT3-ITD (overall survial 69% [95% CI 62-77] in the monitoring group and 78% [70-87] in the no monitoring group; HR 1·56, 95% CI 0·96-2·52) or those with fusion gene transcripts (overall survial 72% [95% CI 65-79] in the monitoring group and 77% [68-87] in the no monitoring group; HR 1·28, 95% CI 0·80-2·18).
    INTERPRETATION: Sequential molecular MRD monitoring, coupled with MRD-guided treatment, did not improve overall survival in the entire study population; however, in the subgroup of patients with baseline NPM1 and FLT3 ITD mutations, we observed a survival benefit for MRD monitoring.
    FUNDING: National Institute for Health Research, Blood Cancer UK, and Cancer Research UK.
    DOI:  https://doi.org/10.1016/S2352-3026(25)00037-7
  10. medRxiv. 2025 Apr 26. pii: 2025.04.11.25325281. [Epub ahead of print]
    Somatic TP53 Mutations Drive T and NK Cell Dysfunction in AML and Can be Rescued by Reactivating Wild Type p53.
    Li Li, Muharrem Muftuoglu, Edward Ayoub, Jiangxing Lv, Mahesh Basyal, Aram Bidikian, Ran Zhao, Menon Prashant, Po Yee Mak, Rupesh K Kesharwani, Yuki Nishida, Ghayas C Issa, Navin Varadarajan, Bing Carter, Michael Andreeff.
      Therapeutic advances in immunotherapy have significantly improved outcomes in lymphomas and myelomas, yet patients with TP53-mutant acute myeloid leukemia (AML) continue to be challenged. While TP53 mutations in leukemic blasts have been extensively characterized, their incidence and impact within immune cells remain largely unexplored. Here, using single-cell multi-omics and integrated phenotypic analyses, we identify TP53 mutations in T and NK cells from AML patients. Notably, T cells harboring monoallelic TP53 mutations exhibited elevated proliferative markers yet showed reduced cytotoxic capacity and increased expression of inhibitory receptors, including PD-1, TIGIT, and TIM-3. To investigate the functional consequences of p53-mutant immune cells, we engineered CAR-T cells carrying clinically relevant p53 mutations (Y220C and R175H). These mutant p53 CAR-T cells exhibited a pronounced exhaustion phenotype, with diminished cytokine secretion and impaired tumor cytolysis both in vitro and in PDX mouse models. Crucially, restoring mutant p53 to a wild-type conformation using a targeted small-molecule reactivator rescued CAR-T functionality, reduced exhaustion marker expression, and prolonged survival in AML PDX mouse models, revealing a direct mechanistic link between TP53 mutations in T cells and therapeutic resistance. Our findings establish TP53-mutant T cells as a previously unrecognized driver of immune escape in AML, highlighting the importance of immune-cell genotyping and p53 reactivation strategies. By demonstrating that mutant p53 can be selectively corrected to restore T-cell function, this study opens new avenues for immunotherapeutic intervention in TP53-mutant AML.
    DOI:  https://doi.org/10.1101/2025.04.11.25325281
  11. Haematologica. 2025 Apr 30.
    Clinical characteristics and therapeutic determinants of RUNX1::RUNX1T1 differ from those of CBFB::MYH11 acute myeloid leukemia.
    Miao Yang, Wenting Wang, Guangji Zhang, Shaowei Qiu, Bingcheng Liu, Yingchang Mi, Ying Wang, Jianxiang Wang, Hui Wei.
      Core binding factor acute myeloid leukemia (CBF-AML) includes RUNX1::RUNX1T1 and CBFB::MYH11 AML. To investigate whether they should be regarded as distinct entities and treated separately, we retrospectively analyzed 536 patients with CBF-AML aged 60 years or younger. For CBFB::MYH11 AML, no outcome differences were observed between standard-dose (SD) and intermediate-dose (ID) cytarabine induction, with 5-year overall survival (OS) and relapse-free survival (RFS) at 86.4% vs. 85.3% (P=0.99) and 74.1% vs. 68.4% (P=0.93), respectively. However, ID induction improved the outcomes of RUNX1::RUNX1T1 AML, with 5-year OS and RFS rates of 77.7% vs. 60.3% (P.
    DOI:  https://doi.org/10.3324/haematol.2024.287293
  12. Blood Adv. 2025 Apr 30. pii: bloodadvances.2025015964. [Epub ahead of print]
    Impact of Post-Transplant Cyclophosphamide-Based GVHD Prophylaxis in Patients 70 years and Older: An Update from BMT CTN 1703.
    Sameem M Abedin, Michael J Martens, Javier Bolaños-Meade, Monzr M Al Malki, Qinghua Lian, Lyndsey Runaas, Hany Elmariah, Mahasweta Gooptu, Karilyn Larkin, Brian C Shaffer, Alison W Loren, Melhem M Solh, Amin Majid Alousi, Omer Jamy, Miguel-Angel Perales, Andrew R Rezvani, Ami S Bhatt, Najla El Jurdi, Janny M Yao, Kristy Applegate, Leslie S Kean, Yvonne A Efebera, Ran Reshef, William Bennett Clark, Eric Leifer, Wael Saber, Mary M Horowitz, Richard J Jones, Shernan G Holtan, Mehdi Hamadani.
      Allogeneic hematopoietic cell transplant (allo-HCT) is underutilized in adults aged ≥ 70 years. Morbidity, often driven by graft-vs-host disease (GVHD), is considered a major barrier to its use. BMT CTN 1703 randomly assigned adults with hematologic malignancies undergoing allo-HCT after reduced intensity conditioning to receive either post-transplant cyclophosphamide, mycophenolate mofetil, and tacrolimus (PTCy) or tacrolimus and methotrexate (Tac/MTX) for GVHD prophylaxis. Overall study results revealed superior GVHD-free, relapse-free survival (GRFS) with PTCy-based prophylaxis. This analysis explored the impact of PTCy in patients ≥ 70 years enrolled to BMT CTN 1703. We analyzed outcomes for 96 patients aged ≥ 70 years. PTCy maintained superiority for the primary endpoint with a GRFS rate of 67.1% compared to 29.5% with Tac/MTX (p=0.001). GVHD control and improved immunosuppression-free survival contributed to a lower 1-year non-relapse mortality (NRM) with PTCy. Further, lower rates of relapse/progression were observed with PTCy, altogether resulting in significantly improved adjusted 1-year survival with PTCy at 94.3% versus 60.2% with Tac/MTX (p=0.001). PTCy based GVHD prophylaxis should be considered standard prophylaxis for older adults. Given low rates of NRM and excellent survival outcomes with this approach, there should be greater consideration for allo-HCT in older patients, particularly patients ≥ 70 years.
    DOI:  https://doi.org/10.1182/bloodadvances.2025015964
  13. Exp Hematol Oncol. 2025 Apr 26. 14(1): 61
    Hypomethylating agents plus venetoclax for high-risk MDS and CMML as bridge therapy to transplant: a GESMD study.
    Ines Zugasti, Monica Lopez-Guerra, Sandra Castaño-Díez, Daniel Esteban, Alejandro Avendaño, Helena Pomares, Ana Perez, Sara García-Ávila, Irene Padilla Conejo, Cristina de la Fuente Montes, Alexandra Martínez-Roca, Beatriz Merchán, Carlos Jiménez-Vicente, Francesca Guijarro, Jose Ramón Álamo, Albert Cortes-Bullich, Victor Torrecillas, Lucia Mont, Esther Carcelero, Gisela Riu, Lurdes Zamora, Joan Bargay, Ana Triguero, Maria Suarez-Lledó, Maria Queralt Salas, Felix López-Cadenas, Fernando Ramos, Blanca Xicoy, David Valcárcel, Montserrat Arnan, Carmen Martínez, Montserrat Rovira, Francesc Fernández-Avilés, Maria Díez-Campelo, Jordi Esteve, Marina Díaz-Beyá.
       BACKGROUND: High-risk myelodysplastic syndromes (HR-MDS) and chronic myelomonocytic leukemia (CMML) remain therapeutic challenges with suboptimal outcomes. The only potentially curative treatment is allogeneic stem cell transplantation (allo-SCT). The most frequent pre-allo-SCT treatment is monotherapy with hypomethylating agents (HMA), but approximately 40% of patients cannot proceed to allo-SCT, mainly due to disease progression. Recent evidence suggests that combining HMA with venetoclax (HMA/VEN) could increase HMA efficacy in HR-MDS but it remains unclear if this combination could bridge more patients to allo-SCT.
    METHODS: We retrospectively evaluated HMA/VEN as a bridge to allo-SCT in 30 patients with HR-MDS or CMML eligible for transplant. Eighteen patients were treatment-naïve and 12 were refractory or relapsed (R/R).
    RESULTS: As defined by the IWG 2023 criteria, the overall response rate (ORR) was 90% and the composite complete response rate was 77%. For the R/R patients, ORR was 83%. The allo-SCT rate was 83%, and the allo-SCT rate of those patients treated exclusively with HMA/VEN without further bridge therapies was 76%. One- and two-year post-allo-SCT survival was 75% and two-year cumulative incidence of relapse was 30.5%. Follow-up of measurable residual disease identified some molecular relapses that were controlled with preemptive treatment.
    CONCLUSIONS: Our findings indicate that HMA/VEN combination therapy shows promise as a bridging strategy to allo-SCT in HR-MDS and CMML.
    Keywords:  Allo-SCT; Bridge therapy; CMML; Cytoreductive therapy; HMA/VEN; MDS; MDS/MPN; MRD; Molecular follow-up
    DOI:  https://doi.org/10.1186/s40164-025-00652-5
  14. Leuk Lymphoma. 2025 Apr 30. 1-4
    A case series of oral decitabine-cedazuridine with venetoclax for blastic plasmacytoid dendritic cell neoplasm.
    Hannah Goulart, Guillermo Garcia-Manero, Tapan M Kadia, Naval Daver, Courtney D DiNardo, Farhad Ravandi, Muzaffar Qazilbash, Caitlin Rausch, Gabriela Llaurador Caraballo, Sherry Pierce, Naveen Pemmaraju.
      
    Keywords:  Myeloid leukemias and dysplasias; chemotherapeutic approaches; pharmacotherapeutics
    DOI:  https://doi.org/10.1080/10428194.2025.2498046
  15. Haematologica. 2025 Apr 30.
    Different features of acute myeloid leukemia stem cell quantification in intensively treated patients.
    Lok Lam Ngai, Tom Reuvekamp, Diana Hanekamp, Fleur Janssen, Laura Oudshoorn-van Marsbergen, Jannemieke Carbaat-Ham, Maaike A M Hofland, Mona M H E Fayed, Angèle Kelder, Willemijn J Scholten, Alexander N Snel, Costa Bachas, Jesse M Tettero, Dimitri A Breems, Thomas Fischer, Bjørn T Gjertsen, Laimonas Griškevičius, Gunnar Juliusson, Arjan A Van de Loosdrecht, Johan A Maertens, Markus G Manz, Thomas Pabst, Jakob R Passweg, Kimmo Porkka, Peter J M Valk, Patrycja Gradowska, Bob Löwenberg, Gert J Ossenkoppele, David C De Leeuw, Jacqueline Cloos.
      In acute myeloid leukemia, the burden of CD34+CD38- leukemia stem cells (LSC) has prognostic value at diagnosis and after induction chemotherapy. Since different methods of LSC quantification have been proposed, we determined the prognostic value on overall survival and incidence of relapse of these methods across ELN2017 risk groups, using data from the HOVON-SAKK132 trial. In addition, we have evaluated the optimal number of acquired white blood cells for accurate LSC detection and the prognostic value of individual LSC markers. Results show that acquiring 1 million white blood cells is essential for accurate LSC-negativity assessment. Among different LSC markers, CD44 overexpression on CD34+CD38- cells was the only insignificant marker in our panel. Testing the impact of several published variations on the analysis for LSC assessments on prognostic value for overall survival and cumulative incidence of relapse, showed marginal differences, demonstrating the robust prognostic value of LSC burden. For further clinical implementation, the optimal LSC assessment may differ among ELN risk groups. In conclusion, LSC burden is a robust prognostic factor and insight in the different methods of LSC definition can facilitate the clinical implementation.
    DOI:  https://doi.org/10.3324/haematol.2024.287090
  16. Am J Hematol. 2025 Apr 29.
    A Phase II Trial of Geriatric Assessment-Guided Selection of Treatment Intensity in Older Adults With AML.
    Vijaya R Bhatt, Christopher S Wichman, Thuy T Koll, Alfred L Fisher, Tanya M Wildes, Michael Haddadin, Ann M Berger, James O Armitage, Sarah A Holstein, Lori J Maness, Krishna Gundabolu.
      How to select the appropriate intensity of chemotherapy in older adults with acute myeloid leukemia (AML) remains an unanswered question. In a phase II trial of older adults ≥ 60 years with AML (n = 73), we used geriatric assessment (measures of comorbidity burden, physical and cognitive function) to determine fitness for intensive chemotherapy. We integrated the geriatric assessment and genetic test results to personalize the selection of chemotherapy intensity with a goal to reduce early mortality (NCT03226418). Broad eligibility criteria allowed enrolling patients representative of those treated in real-world practices: 45% of patients were ≥ 70 years, 57% had ≥ 2 comorbidities, 27% had a history of solid malignancies, and 74% had impairments in ≥ 2 geriatric assessment domains used to assign treatment intensity. Thirty-two percent of patients resided in rural areas, and 45% were comanaged with community oncologists. The median time from enrollment to therapy initiation was 1 day (range 0-13). Eight patients (11%) received intensive chemotherapy; others received low-intensity chemotherapy. Mortality at 30 days from diagnosis was 6.8% (95% confidence interval, CI 3.0%-15.1%) and at 90 days was 21.9% (95% CI 14.0%-32.7%). One-year survival was 45.9% (95% CI 35.6%-59.3%). Our study demonstrates that pre-treatment geriatric assessment in older adults with AML is feasible, can identify several functional impairments, and guide the selection of treatment intensity. A randomized trial is necessary to confirm the survival benefit of this approach over the traditional approach of treatment selection. Trial Registration: NCT03226418.
    Keywords:  acute myeloid leukemia; geriatric assessment; mortality; older adults; precision oncology
    DOI:  https://doi.org/10.1002/ajh.27694
  17. J Clin Invest. 2025 May 01. pii: e184431. [Epub ahead of print]135(9):
    Inborn errors of immunity underlie clonal T cell expansions in large granular lymphocyte leukemia.
    Carlos Bravo-Perez, Carmelo Gurnari, Jani Huuhtanen, Naomi Kawashima, Luca Guarnera, Aashray Mandala, Nakisha D Williams, Christopher Haddad, Michaela Witt, Serhan Unlu, Zachary Brady, Olisaemeka Ogbue, Mark Orland, Arooj Ahmed, Yasuo Kubota, Simona Pagliuca, Arda Durmaz, Satu Mustjoki, Valeria Visconte, Jaroslaw P Maciejewski.
      BACKGROUNDT cell large granular lymphocyte leukemia (T-LGLL) is a lymphoproliferative disorder of cytotoxic T lymphocytes (CTLs), often with gain-of-function STAT3 mutations. T-LGLL represents a unique model for the study of persistent CTL expansions. Albeit autoimmunity is implied, various paradoxical observations led us to investigate whether immunodeficiency traits underpin T-LGLL.METHODSThis is a comprehensive immunogenomic study of 92 consecutive patients from a large T-LGLL cohort with full laboratory-clinical characterization (n = 271). Whole-exome profiling of variants associated with inborn errors of immunity (IEI) and somatic mutations in T cell lymphoid drivers was analyzed. Single-cell RNA-Seq and TCR-Seq in T-LGLL samples and RNA-Seq in T cell cancer cell lines were utilized to establish biological correlations.RESULTSLymphocytopenia and/or hypogammaglobulinemia were identified in 186 of 241 (77%) T-LGLL patients. Genetic screening for IEI revealed 43 rare heterozygous variants in 38 different immune genes in 34 of 92 (36%) patients (vs. 167/63,026 [0.26%] in controls). High-confidence deleterious variants associated with dominant, adult-onset IEIs were detected in 15 of 92 (16%) patients. Carriers showed atypical features otherwise tied to the cryptic IEI, such as earlier onset, lower lymphocyte counts, lower STAT3 mutational rate, and higher proportions of hypogammaglobulinemia and immune cytopenia/bone marrow failure than noncarriers. Somatic mutational landscape, RNA-Seq, and TCR-Seq analyses supported immune imbalance caused by the IEI variants and interactions with somatic mutations in T cell lymphoid drivers.CONCLUSIONSOur findings in T-LGLL reveal that maladaptive CTL expansions may stem from cryptic immunodeficiency traits and open the horizon of IEIs to clonal hematopoiesis and bone marrow failure.FUNDINGNIH; Aplastic Anemia and MDS International Foundation; VeloSano; Edward P. Evans Foundation; Instituto de Salud Carlos III; European Research Council; European Research Area Network on Personalised Medicine; Academy Finland; Cancer Foundation Finland.
    Keywords:  Adaptive immunity; Genetics; Hematology; Lymphomas; Molecular genetics
    DOI:  https://doi.org/10.1172/JCI184431
  18. EMBO Rep. 2025 Apr 28.
    DDB1 engagement defines the selectivity of S656 analogs for cyclin K degradation over CDK inhibition.
    Céline Moison, Rodrigo Mendoza-Sanchez, Deanne Gracias, Doris A Schuetz, Jean-François Spinella, Simon Girard, Bounkham Thavonekham, Jalila Chagraoui, Aurélie Durand, Simon Fortier, Tara MacRae, Eric Bonneil, Yannick Rose, Nadine Mayotte, Isabel Boivin, Pierre Thibault, Josée Hébert, Réjean Ruel, Anne Marinier, Guy Sauvageau.
      In efforts to identify additional therapeutic targets for Acute Myeloid Leukemia (AML), we performed a high-throughput screen that includes 56 primary specimens tested with 10,000 structurally diverse small molecules. One specific hit, called S656 acts as a molecular glue degrader (MGD), that mediates the CRL4-dependent proteolysis of cyclin K. Structurally, S656 features a moiety that binds to the ATP binding site of cyclin-dependent kinases (CDKs), allowing the recruitment of the CDK12-cyclin K complex, along with a binding site for DDB1 bridging the CRL4 complex. Structure activity relationship studies reveal that minimal modifications to the dimethylaniline moiety of S656 improve its cyclin K MGD function over CDK inhibition by promoting DDB1 engagement. This includes full occupation of the DDB1 pocket, preferably with hydrophobic terminal groups, and cation-π interaction with Arg928. Additionally, we demonstrate that despite structural diversity, cyclin K degraders exhibit similar functional activity in AML which is distinct from direct CDK12 inhibition.
    Keywords:  Acute Myeloid Leukemia; CDK12; Cyclin K; DDB1; Molecular Glue Degrader
    DOI:  https://doi.org/10.1038/s44319-025-00448-y
  19. Sci Adv. 2025 May 02. 11(18): eadt9846
    Clonal hematopoiesis is associated with distinct rheumatoid arthritis phenotypes.
    FinnGen
      Clonal hematopoiesis (CH) becomes more prevalent with aging and may influence inflammatory diseases by altering immune function. While CH of indeterminate potential (CHIP) promotes inflammation in nonmalignant conditions, its relationship with rheumatoid arthritis (RA) remains unknown. We analyzed CHIP mutations in RA using two population-level cohorts and patients with newly diagnosed RA. CHIP was associated with prevalent RA in 10,089 FINRISK study participants with whole-exome sequencing (OR, 2.06; P = 0.029) and in the FinnGen cohort (n = 520,210; OR, 1.49; P < 0.001) using single-nucleotide polymorphism array-based CHIP annotation. In FinnGen, CHIP was also associated with inferior overall survival in participants with RA (P = 0.013). In newly diagnosed RA (n = 573), DNMT3A-mutated seropositive patients had increased inflammatory markers and disease activity compared with patients without CHIP. In contrast, TET2 mutations were enriched in seronegative RA (P = 0.009). Our findings provide further evidence for the context-dependent association between CHIP and inflammation, with potential therapeutic implications.
    DOI:  https://doi.org/10.1126/sciadv.adt9846
  20. Ann Hematol. 2025 Apr 27.
    Molecular predictors of venous and arterial thrombotic events in patients with myelofibrosis.
    Olga Morath, Jenny Rinke, Annabell Walter, Carl Crodel, Manja Meggendorfer, Constance Baer, Andreas Hochhaus, Thomas Ernst.
      While patients with myelofibrosis (MF) face an elevated risk of thrombosis, no validated scoring system currently exists to effectively assess this specific risk. This study aimed to explore distinct molecular risk factors for arterial (ATE) and venous (VTE) thrombosis in a cohort of 141 MF patients. Mutation analysis was performed by next-generation sequencing for a panel of 30 target myeloid genes as previously described: 137 driver and 164 non-driver mutations were detected. JAK2-V617F was identified in 77 (55%) patients, CALR in 45 (32%) patients, and seven (5%) patients carried an MPL variant. Patients #58 and #60 harbored JAK2-V617F and MPL; and patient #67 was positive for all three driver genes. The JAK2-V617F variant allele frequency (VAF) was assessed in 66/80 patients, revealing a median of 34.0% (range, 5.0-96.0). ASXL1 (n = 34 patients) were the most common non-driver mutations, followed by TET2 (n = 26), U2AF1 (n = 12), and DNMT3A (n = 11). During a median follow up of 4.8 years, 24 (17%) patients experienced VTE, 15 (11%) ATE, and two patients experienced both. Among the 24 patients with VTE, 12 (50%) experienced splanchnic vein thrombosis. The JAK2-V617F mutation was associated with VTE (OR 2.6, 95% CI 1.01-7.16), while the DNMT3A mutation was an independent predictor of ATE (OR 5.40, 95% CI 1.30-22.42). High JAK2-V617F VAF (> 50%) was not related with an increased thrombotic risk. Results of this study demonstrate the significance of DNMT3A mutations as an independent molecular risk factor for ATE, highlighting the potential to include these somatic non-driver mutations in future thrombosis risk scores.
    Keywords:   DNMT3A ; JAK2 ; Myelofibrosis; Thrombosis
    DOI:  https://doi.org/10.1007/s00277-025-06361-7
  21. Exp Hematol. 2025 Apr 30. pii: S0301-472X(25)00083-9. [Epub ahead of print] 104792
    Distinct transcriptional changes in hematopoietic progenitor subsets upon LPS-induced emergency granulopoiesis.
    Sladjana Kosanovic, Karolina Vanickova, Mirko Milosevic, Irina Ribeiro Bas, Mateusz Chilinski, Dariusz Plewczynski, Petr Danek, Jakub Rohlena, Katerina Rohlenova, Meritxell Alberich-Jorda.
      Emergency granulopoiesis is a critical process by which hematopoietic progenitors and stem cells facilitate enhanced granulocytic production during severe infections. However, the role of distinct multipotent progenitors (MPPs) at early stages of this process remains underexplored. Here, we investigated the contribution of MPPs to granulocytic production following lipopolysaccharide (LPS) administration in wild-type mice, simulating a bacterial infection. Transplantation assays demonstrated that LPS exposure reduces the engraftment capacity of lymphoid-biased MPP4 and enhances lymphoid production, rather than supporting myeloid lineage output. Further, single-cell RNA sequencing (scRNA-seq) of MPPs isolated from control and LPS challenged mice revealed transcriptional reprogramming of non-lineage committed MPPs towards myeloid- and erythroid-biased progenitors. Notably, inflammatory progenitor populations emerged upon activation of LPS-induced emergency granulopoiesis, displaying chromatin accessibility changes that align with a commitment to myeloid and erythroid fates. Pseudotime analysis elucidated cellular trajectories that suggest a developmental pathway where unbiased progenitors, present in non-stress conditions, transition towards myeloid and erythroid lineage outputs upon LPS administration. In line with our functional MPP4 assessment, scRNA-seq suggested that lymphoid-biased progenitors do not transcriptionally rewire during early stages of emergency granulopoiesis. Collectively, our data highlight the critical role of specific MPP subsets in responding to LPS-induced inflammatory signals and underscore the dynamic adaptations that occur during granulocyte production in response to infection.
    Keywords:  ATACseq; Emergency Granulopoiesis; Hematopoietic stem cell; Progenitors; lipopolysaccharide; scRNAseq
    DOI:  https://doi.org/10.1016/j.exphem.2025.104792
  22. J Clin Oncol. 2025 Apr 28. JCO2401841
    Hematopoietic Stem Cell Transplantation Outcomes for High-Risk AML: A Report From the Children's Oncology Group.
    Benjamin J Huang, Lauren K Meyer, Todd A Alonzo, Yi-Cheng Wang, Adam J Lamble, Rhonda E Ries, Weijie Wang, Betsy Hirsch, Gordana Raca, Xiaotu Ma, Alan S Gamis, Richard Aplenc, E Anders Kolb, Todd M Cooper, Katherine Tarlock, Michael R Loken, Soheil Meshinchi, Joseph H Chewning, William G Woods, John T Horan.
       PURPOSE: Hematopoietic stem cell transplantation (HSCT) is used as consolidation for pediatric patients with high-risk AML in first complete remission (CR1). The definition of high-risk AML has evolved considerably over the past two decades with the successive identification of new unfavorable risk factors. We conducted a cross-study analysis to determine whether HSCT improves the outcomes of patients with contemporarily defined high-risk AML.
    METHODS: We combined data from AAML0531 and AAML1031, the last two phase III clinical trials completed by the Children's Oncology Group (COG). These two trials established the prognostic importance of measurable residual disease (MRD) and several high-risk cryptic cytogenetic/molecular (CM) alterations, which were applied to reclassify patients in the current COG phase III clinical trial, AAML1831. We compared the outcomes after HSCT in CR1 with those after chemotherapy alone in CR1 in the redefined high-risk group.
    RESULTS: Our study cohort comprised 463 patients with high-risk CM alterations and 72 patients with standard-risk (SR) CM results with positive MRD at end of induction I. In all, 33.9% and 45.8% of these groups underwent HSCT in CR1, respectively. HSCT was associated with decreased relapse and improved disease-free survival (DFS) in both groups. In the high-risk CM group, 5-year DFS was 26.0% (95% CI, 20.6 to 31.6) and 49.8% (95% CI, 41.7 to 57.4; P < .001) in patients receiving chemotherapy alone and HSCT, respectively. In the SR CM and MRD+ groups, DFS was 16.9% (95% CI, 4.3 to 36.7) compared with 50.9% (95% CI, 32.7 to 66.5; P = .032). HSCT was also associated with improvement in outcomes based on multivariable analysis and across subgroups defined by clinical trial and by high-risk CM subtype, with the exception of chromosome 7 or 5 loss.
    CONCLUSION: HSCT was associated with improved outcomes in pediatric patients with contemporarily defined high-risk AML.
    DOI:  https://doi.org/10.1200/JCO-24-01841
  23. Eur J Med Res. 2025 May 02. 30(1): 354
    Impact of KIT mutation on efficacy of venetoclax and hypomethylating agents in newly diagnosed acute myeloid leukemia.
    Wenxiu Shu, Qianqian Yang, Donghua He, Yi Li, Jing Le, Qianqian Cai, Hui Dai, Liufei Luo, Bingrong Chen, Yuan Gong, Dian Jin.
       BACKGROUND: The combination of venetoclax (VEN) with hypomethylating agents (HMAs) has emerged as a new standard treatment for older or unfit patients with acute myeloid leukemia (AML). However, the predictive factors for VEN/HMA efficacy remain unclear. In our study, we performed the first analysis of the impact of KIT mutations on therapeutic outcomes in newly diagnosed AML patients undergoing VEN/HMA regimens.
    METHODS: In this retrospective study, we included 16 KIT-mutant AML patients receiving VEN/HMA (Cohort A), 141 KIT-wild-type AML patients receiving VEN/HMA (Cohort B), and 69 KIT-mutant AML patients receiving intensive chemotherapy (IC) (Cohort C). We compared the differences in therapeutic efficacy among the different cohorts. Furthermore, we conducted multivariate analyses in patients receiving VEN/HMA to identify factors influencing therapeutic outcomes.
    RESULTS: Compared to Cohort B, Cohort A exhibited significantly lower overall response rate (ORR) (18.8% vs. 72.3%, p < 0.001) and measurable residual disease (MRD) negativity rate (18.8% vs. 68.1%, p < 0.001), with a shorter median event-free survival (EFS) (1.9 months vs. 7.8 months, p < 0.001). No significant difference in overall survival (OS) was observed. Among KIT-mutant patients, IC showed superior ORR (78.3% vs. 18.8%, p < 0.001), MRD negativity rate (75.4% vs. 18.8%, p < 0.001), and EFS (12.2 months vs. 1.9 months, p < 0.001) compared to VEN/HMA. No significant difference in OS was observed between the two cohorts. Multivariate analysis confirmed KIT mutations as an independent predictor of lower ORR (OR 0.020, 95% CI 0.002-0.211, p = 0.001) and shorter EFS (HR 6.318, 95% CI 2.659-15.012, p < 0.001).
    CONCLUSIONS: Our findings suggest that KIT mutations are associated with poor response and shorter EFS in AML patients treated with VEN/HMA, highlighting the importance of KIT mutation status in risk stratification and treatment selection.
    Keywords:  Acute myeloid leukemia; Chemotherapy; Hypomethylating agents; KIT; Prognosis; Venetoclax
    DOI:  https://doi.org/10.1186/s40001-025-02637-w
  24. Br J Haematol. 2025 Apr 30.
    Contemporary management paradigms and emerging therapeutics for myelodysplastic syndromes/neoplasms.
    Ramkarthic Ramanathan, Yiyu Xie, Talha Badar, Amer M Zeidan, Shyam A Patel.
      From a historical perspective, the treatment landscape of myelodysplastic syndromes/neoplasms (MDS) has experienced a standstill in terms of new approvals by the U.S. Food and Drug Administration up until the recent 5 years. The widespread availability of comprehensive genome sequencing has shed insight into human MDS biology toward the goal of rational therapeutic design. This new knowledge has inspired the development of investigational therapies that extend beyond the scope of traditional erythropoiesis-stimulating agents and hypomethylating agents. We describe how these contemporary treatment options are changing the management paradigms for lower-risk and higher-risk MDS, based on the landmark trial data. We discuss investigational therapies in the MDS pipeline, such as venetoclax, emavusertib, canakinumab and olutasidenib. We highlight challenges and solutions to the successful translation of emerging therapies based on our improved understanding of the biology of MDS, including the genomics of MDS with mutated TP53. We discuss how the identification of biomarkers of response to therapeutics may help guide clinical trial design for certain subsets of patients. Finally, we discuss how multicentre randomized trials can help facilitate the clinical rollout of emerging MDS therapeutics.
    Keywords:  imetelstat; luspatercept; myelodysplastic syndromes/neoplasms (MDS); targeted therapies
    DOI:  https://doi.org/10.1111/bjh.20116
  25. Ann Hematol. 2025 Apr 29.
    Phase-1 study of vamotinib (PF-114), a 3rd generation BCR::ABL1 tyrosine kinase-inhibitor, in chronic myeloid leukaemia.
    Anna Turkina, Olga Vinogradova, Elza Lomaia, Evgeniya Shatokhina, Oleg Shukhov, Ekaterina Chelysheva, Dzhariyat Shikhbabaeva, Irina Nemchenko, Anna Petrova, Anastasiya Bykova, Nadiya Siordiya, Vasily Shuvaev, Ilya Mikhailov, Fedor Novikov, Veronika Shulgina, Andreas Hochhaus, Oliver Ottmann, Jorge Cortes, Robert Peter Gale, Ghermes Chilov.
      Vamotinib (PF-114) is a 3rd -generation, ATP-competitive oral tyrosine kinase inhibitor (TKI) active against wild-type and mutated BCR::ABL1 isoforms including BCR::ABL1T315I. We present final results of a phase-1 vamotinib dose-escalation study to identify maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) followed by expansion cohorts. 51 subjects with chronic myeloid leukaemia (CML) failing ≥ 1 2nd generation TKI or with BCR::ABL1T315I were enrolled. Subjects received vamotinib, 50-750 mg/d, continuously. Median exposure was 6 months (range, < 1-52 months). Median CML duration pre-study was 10 years (range, < 1-23 years). 27 subjects received ≥ 3 prior TKIs and 16 had BCR::ABL1T315I. The MTD was 600 mg with the Grade-3 psoriasis-like skin toxicity as the DLT. There were no vascular occlusive events nor deviations of ankle-brachial index. Complete haematologic response (CHR) was achieved in 14 of 30 subjects, major cytogenetic response (MCyR) in 14 of 44 subjects, complete cytogenetic response (CCyR) in 10 of 50 and major molecular response (MMR) in 7 of 51 subjects who did not have a CHR, MCyR, CCyR or MMR at enrollment. The best safety/efficacy dose was 300 mg with MCyR achieved in 6 of 7 subjects, CCyR in 5 of 9 and MMR in 4 of 9 subjects who did not have a MCyR, CCyR or MMR at enrollment. 5 of 16 subjects with BCR::ABL1T315I responded including 3 achieving a CHR, 3, a MCyR, and 1,a CCyR. 2 of 5 subjects failing ponatinib achieved a CHR. Vamotinib dose for further phase-3 study is 300 mg/d.
    DOI:  https://doi.org/10.1007/s00277-025-06239-8
  26. Blood Cancer Discov. 2025 Apr 28. OF1-OF4
    Putting AML Differentiation States on the BoneMarrowMap.
    Jonas Berger, Livius Penter.
      This article presents a novel computational tool, "BoneMarrowMap," that enables the mapping of leukemic single-cell RNA sequencing datasets to hematopoietic differentiation states. By utilizing BoneMarrowMap for a large-scale single-cell RNA sequencing reanalysis, the authors discover 12 recurrent acute myeloid leukemia differentiation patterns linked to prognosis and treatment and dissect leukemic clonal architectures within individual patients. See related article by Zeng and colleagues, p. XX.
    DOI:  https://doi.org/10.1158/2643-3230.BCD-25-0083
  27. Leukemia. 2025 Apr 29.
    Is the bone marrow microenvironment the hidden catalyst in malignant haematopoiesis?
    Syed A Mian, Steven Ngo, Dominique Bonnet.
      
    DOI:  https://doi.org/10.1038/s41375-025-02630-6
  28. Nat Commun. 2025 Apr 30. 16(1): 4043
    Network-based clustering unveils interconnected landscapes of genomic and clinical features across myeloid malignancies.
    Fritz Bayer, Marco Roncador, Giusi Moffa, Kiyomi Morita, Koichi Takahashi, Niko Beerenwinkel, Jack Kuipers.
      Myeloid malignancies exhibit considerable heterogeneity with overlapping clinical and genetic features among subtypes. We present a data-driven approach that integrates mutational features and clinical covariates at diagnosis within networks of their probabilistic relationships, enabling the discovery of patient subgroups. A key strength is its ability to include presumed causal directions in the edges linking clinical and mutational features, and account for them aptly in the clustering. In a cohort of 1323 patients, we identify subgroups that outperform established risk classifications in prognostic accuracy. Our approach generalises well to unseen cohorts with classification based on our subgroups similarly offering advantages in predicting prognosis. Our findings suggest that mutational patterns are often shared across myeloid malignancies, with distinct subtypes potentially representing evolutionary stages en route to leukemia. With pancancer TCGA data, we observe that our modelling framework extends naturally to other cancer types while still offering improvements in subgroup discovery.
    DOI:  https://doi.org/10.1038/s41467-025-59374-1
  29. Cell. 2025 May 01. pii: S0092-8674(25)00401-5. [Epub ahead of print]188(9): 2309-2311
    Mutant macrophages CHIP in to help solid tumors.
    Isak W Tengesdal, Siddhartha Jaiswal.
      Clonal hematopoiesis of indeterminate potential (CHIP) promotes adverse outcomes in age-related diseases. However, the impact of CHIP on solid tumors has yet to be elucidated in large-scale cancer-focused cohorts. In a recently published article in the New England Journal of Medicine, Pich et al. provide evidence for a tumor-promoting role of CHIP in solid malignancies.
    DOI:  https://doi.org/10.1016/j.cell.2025.03.049
  30. Haematologica. 2025 Apr 30.
    Optimizing olverembatinib dose in chronic phase chronic myeloid leukemia.
    Xiaoshuai Zhang, Yunfan Yang, Bingcheng Liu, Xin Du, Xiaodong Wang, Huanling Zhu, Lu Yu, Zongru Li, Shasha Zhao, Linhua Yang, Yanping Ma, Li Meng, Yanqing Zhang, Guohui Li, Lijie Yang, Baohong Wang, Xuehong Ran, Jian Huang, Na Gao, Qin Wen, Yan Wen, Yuxia Zhao, Yu Zhu, Yanqiu Han, Zhenfang Liu, Xin Du, Jianyu Weng, Robert Peter Gale, Li Zhou, Yanli Zhang, Qian Jiang.
      Optimizing olverembatinib dose in people with chronic phase chronic myeloid leukemia (CML) is important to increase safety without compromising efficacy. We designed a multi-center retrospective study comparing safety and efficacy of olverembatinib between the recommended dose of 40 mg every other day (QOD; N = 216) and a reduced dose of 30 mg QOD (N = 66) in subjects failing other tyrosine kinase-inhibitors (TKIs). The cohorts were similar in baseline co-variates and adjusted for by propensity score matching (PSM). There were no significant differences in cytogenetic and molecular responses, as well as outcomes between the 2 dose cohorts. However, the proportion of subjects receiving the original olverembatinib dose at the last follow-up was significantly higher in the 30 mg cohort (64% [95%Confidence Interval [CI], 53, 75%] versus 44% [37,51%]; p = 0.004). Also, the proportion of subjects receiving a reduced dose or permanently discontinuing because of adverse event was significantly lower in the 30 mg cohort (21% [9, 33%] versus 41% [34, 48%]; p = 0.003). In summary, olverembatinib, 30 mg QOD starting dose is as effective as a 40 mg starting dose but better tolerated in persons with chronic phase CML failing other TKIs.
    DOI:  https://doi.org/10.3324/haematol.2024.287116
  31. Nature. 2025 Apr 30.
    Cell cycle duration determines oncogenic transformation capacity.
    Danian Chen, Suying Lu, Katherine Huang, Joel D Pearson, Marek Pacal, Phillipos Peidis, Sean McCurdy, Tao Yu, Monika Sangwan, Angela Nguyen, Philippe P Monnier, Daniel Schramek, Liang Zhu, David Santamaria, Mariano Barbacid, Nagako Akeno, Kathryn A Wikenheiser-Brokamp, Rod Bremner.
      Oncogenic mutations are widespread in normal human tissues1. Similarly, in murine chimeras, cells carrying an oncogenic lesion contribute normal cells to adult tissues without causing cancer2-4. How lineages that escape cancer via normal development differ from the minority that succumb is unclear. Tumours exhibit characteristic cancer hallmarks; we therefore searched for hallmarks that differentiate cancer-prone lineages from resistant lineages. Here we show that total cell cycle duration (Tc) predicts transformation susceptibility across multiple tumour types. Cancer-prone Rb- and p107-deficient retina (Rb is also known as Rb1 and p107 is also known as Rbl1) exhibited defects in apoptosis, senescence, immune surveillance, angiogenesis, DNA repair, polarity and proliferation. Perturbing the SKP2-p27-CDK2/CDK1 axis could block cancer without affecting these hallmarks. Thus, cancer requires more than the presence of its hallmarks. Notably, every tumour-suppressive mutation that we tested increased Tc, and the Tc of the cell of origin of retinoblastoma cells was half that of resistant lineages. Tc also differentiated the cell of origin in Rb-/- pituitary cancer. In lung, loss of Rb and p53 (also known as Trp53) transforms neuroendocrine cells, whereas KrasG12D or BrafV600E mutations transform alveolar type 2 cells5-7. The shortest Tc consistently identified the cell of origin, regardless of mutation timing. Thus, relative Tc is a hallmark of initiation that distinguishes cancer-prone from cancer-resistant lineages in several settings, explaining how mutated cells escape transformation without inducing apoptosis, senescence or immune surveillance.
    DOI:  https://doi.org/10.1038/s41586-025-08935-x
  32. Am Soc Clin Oncol Educ Book. 2025 Jun;45(3): e473912
    Pegylated Interferons: Still a Major Player for the Treatment of Myeloproliferative Neoplasms.
    Michael Daunov, Rebecca B Klisovic.
      Over the past 35 years, interferons have been explored in various formulations for the management of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), such as essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis, and remain a key tool in caring for patients with these diseases. These agents are excellent cytoreductive agents with high rates of hematologic response, are helpful in symptom management, and have a long track record of safety and manageable toxicities. More recently, they have shown promise in sustaining responses over many years, with associated reductions in driver mutations (JAK2, MPL, CALR) of these diseases, particularly in PV and ET. Since reductions in molecular mutant allele burden have been correlated with several response outcomes such as reductions in both thrombotic risk and disease progression, there is emerging proof that interferons may offer disease-modifying activity. These long-term benefits and their use as the preferred agent in young pregnant women who need cytoreduction make interferons often the first choice in young adult population who harbor a lifetime risk of progression. Looking forward, the prospect of sustained treatment-free responses, like chronic myeloid leukemia after deep molecular response, and normal life expectancy may also be on the frontier. Despite relative rookies such as JAK inhibitors in the MPN landscape, the veteran in the game, interferon, remains a key player.
    DOI:  https://doi.org/10.1200/EDBK-25-473912
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